The most frequent impairments across neural-IgG AE cohorts were found on the measures of visual and verbal learning/memory, attention, processing speed, aspects of executive functions, and complex figure copy. Among NPTs administered in ≥5 studies, impairments were most common in list and figure learning/recall, processing speed, auditory attention/working memory, and executive functions, whereas minimal impairment was observed in most aspects of language and reasoning. Surprisingly, despite obvious temporal lobe involvement in most forms of AE, naming tests were not impaired in any study and may be of minimal utility in this population. This could be due to the fact that naming deficits more often correlate with more lateral temporal regions,41 while AE often involves more mesial temporal dysfunction. However, further study is recommended to confirm the lack of naming impairment in AE.

Although small sample sizes, methodological differences, and test variability limit definitive conclusions regarding test-level impairments and differences across neural antibody groups, some differences in NPT impairment rates between the neural-IgG AE cohorts emerged. Specifically, list learning/memory impairments were common in anti-LGI1 AE (100%) and anti-NMDA-R AE (92%) groups but were present in less than one-third of other groups. By contrast, all groups showed at least 50% impairment on visual memory tasks. Processing speed, auditory attention, response inhibition, and complex figure copy tasks seem more impaired in anti-NMDA-R AE studies (80%, 91%, 57%, and 50%, respectively) compared with anti-LGI1 AE studies (60%, 67%, 33%, and 33%, respectively). These tasks were only examined in 0–2 studies in other cohorts. The rates of verbal fluency impairment were similar between anti-NMDA-R AE and anti-LGI1 AE studies.

Table 4 presents our recommended standardized NPT for AE. At this stage, neural antibody-specific recommendations cannot be made, given the variability in test administration across neural antibodies and sparse data. Given that studies examining NPT in AE remain limited, the use of comprehensive NPT batteries spanning all cognitive domains is recommended.

Recommended Test Battery for Adults With AE

Specific measures which may be of highest yield include (1) tests of visual and verbal learning/memory, (2) basic attention (digit span), (3) processing speed (Symbol-Digit Modalities Test), and (4) executive functions. Regarding memory, the Rey Auditory Verbal Learning Test and Brief Visuospatial Memory Test are recommended over other memory measures given the wide availability of translations and normative data across languages. For testing executive function, we specifically recommended Stroop inhibition and spatial planning (Tower) tests, although the inclusion of multiple executive function tests, such as the Wisconsin Card Sorting Test and Go/No-Go, is encouraged to better characterize executive deficits in AE.

Additional measures which have some support and are recommended for more study include (1) visual attention/working memory (block tapping), (2) sustained attention (continuous performance), (3) verbal fluency, (4) Stroop color and word subtests, (5) block construction, and (6) complex figure copy. We have also included naming tasks in our recommendation as this represents an important domain of cognitive functioning and warrants more study.

This recommended battery may be applied to pediatric populations; however, because very few studies have examined NPT in pediatric AE cohorts and those studies have been limited to patients with anti-NMDA-R AE, more research is needed to further refine recommendations for NPT in pediatric cohorts.

We recommend that NPT be performed at standardized intervals from disease onset, ideally at 6 m, 12 m, and then yearly intervals, to minimize variability between test intervals.

One factor that can influence interpretation of these findings is the frequency of administration of each NPT as it is impossible to determine the utility of tests which have not routinely been studied. When evaluating all AE studies across the United States, Europe, Australia, and Asia as a pooled group, list learning, complex or discrete figure memory, digit span, and verbal fluency tasks were the most used NPTs. Some differences in measures used emerged between neural-IgG AE cohorts. Specifically, there were several measures commonly assessed in anti-NMDA-R AE studies, including digit span, block tapping, fluency, coding, Stroop, planning, block design, comprehension, reasoning, and selective attention, which were not often studied in other neural-IgG AE cohorts. This may reflect the larger number of studies in patients with anti-NMDA-R AE and/or preference of the researchers studying this group.

Interpretation may also be affected using normative vs control comparisons. For example, a recent study of anti-LGI-1 AE patients found that although there were no significant differences between patients and controls on a problem-solving task, 44% of patients demonstrated impairment on that task relative to normative data.3 Using normative data may improve comparability between studies and reduce issues related to small sample sizes. However, there are multiple sets of normative data for each test, and appropriate normative data may vary by country and/or region and could become outdated. In addition, one benefit for using control data is that controls may match patient samples more closely for demographic and socioeconomic factors. Cut-off scores also varied by studies, which limit comparability. It may be useful for studies to report the rates of impairment at multiple cutoffs, including 1 and 1.5 SD below the normative mean, to help determine optimal cutoffs and to improve comparability.

Timing of NPT from symptom onset of treatment may affect performance on NPTs, given expected gradual improvement over time, with greater deficits with a shorter test interval expected. Most studies did not examine the effect of the timing of assessment, except for those including multiple visits, which found improvement over time. Using blanket cut-off scores for impairment, without accounting for the impact of premorbid functioning, may limit detection of clinically significant cognitive decline.

Selection bias may also contribute, with patients who are adherent to therapies and follow up more often referred for NPT. In addition, patients with greater symptoms may be preferentially referred for NPT, skewing the proportion of CI in observational studies. Finally, studies examining NPT in AE have occurred in only a few centers and have primarily involved samples from the United States, Europe, and China, limiting generalizability to other regions/countries and languages.

There is a specific need for additional studies examining executive functions in AE, given significant heterogeneity in specific tests administered across studies. At this stage, inclusion of multiple executive function measures is recommended. Future studies should report test-level data, even if using domain composite scores, to further clarify the sensitivity of specific NPTs in this population. There should also be an effort to standardize analysis and reporting of normative data and cutoffs used. Adjustment for premorbid indicators and/or including measures of subjective cognitive decline could increase the detection of cognitive changes, particularly for patients at the higher end of the spectrum of premorbid ability.

Standardized follow-up intervals would improve comparability between studies. Initial assessment should occur after the acute disease phase (when many patients might not be able to perform a full cognitive assessment) and initial dynamic recovery phase (i.e., a few weeks after the initiation of first-line treatment), and follow-up may be beneficial every 6–12 months in the first 1–2 years of recovery. The number of follow-up assessments should be carefully planned to avoid unnecessary repetitions with increasing test/re-test effects.

As there are differences in pathophysiology between neural antibody-mediated AE, future research should focus on distinct and well-defined (e.g., high titer for GAD65-IgG patients) AE cohorts, rather than pooled cohorts, which may be heterogenous in their neuropsychological outcomes.

Finally, systemic and psychiatric comorbidities, which may significantly contribute to cognitive outcomes, are not typically accounted for in studies reporting cognitive outcomes in AE. Anti-LGI-1 and anti-CASPR2 cohorts may be at greatest risk for undiagnosed concomitant neurodegenerative conditions, given the typically older age of onset compared with other cohorts. Future studies should assess and adjust for these comorbidities in statistical models and use age-matched and sex-matched healthy controls. In addition, in age groups where cognitive disorders, such as mild cognitive impairment, are more prevalent, using matched controls from these cohorts may also be important.

Our search did not reveal any studies of patients with paraneoplastic neurologic disorders manifesting with encephalitis, although research is needed in these groups, to determine whether similar cognitive profiles and testing are applicable. These disorders may differ from the synaptic/extracellular neural antibody-mediated AE due to their cancer association, potential impact of cancer therapies on cognition, and that they are associated with irreversible neuronal destruction and often have a limited response to immunosuppressive therapies.

This review examined NPT's most frequently impaired in neural-IgG seropositive AE cohorts and provided recommendations for a standardized NPT battery. The most impaired NPTs were list and figure learning/recall, processing speed, auditory attention/working memory, and aspects of executive functions, while minimal impairment was observed in most aspects of language and reasoning.

We recommend the use of comprehensive NPT batteries given the dearth of data in this area. At minimum, we recommend inclusion of measures of list learning and figural memory (RAVLT, BVMT), basic attention (digit span), processing speed (SDMT), and multiple executive function measures (particularly Stroop, Tower as well as Wisconsin Card Sorting Test, Go/No-Go—secondary). Measures that may additionally be useful include block tapping, sustained attention (continuous performance), verbal fluency, block construction, and complex figure copy.

We observed several limitations affecting the cognitive research in AE to date including variability in type and frequency of NPTs used. However, these initial recommendations for NPT in AE will help standardize research in this area and facilitate collaboration and compilation of data registries. We further hope that this work encourages future work using more focused and high-yield approaches to identifying meaningful cognitive changes in AE.